This invention relates to a process for the chlorination of carbohydrates and other alcohols. More particular, this invention relates to a process for the preparation of 1,6-dichloro-1,6-dideoxy-.beta.-D-fructofuranosyl-4-chloro-4-deoxy-.alpha. -galactopyranoside. This compound is a potent sweetener, having a sweetness several hundred times that of sucrose. Its use as a sweetener and in sweetening compositions is disclosed in U.S. Pat. No. 4,435,440.
The preparation of 1,6-dichloro-1,6-dideoxy-.beta.-D-fructofuranosyl-4-chloro-4-deoxy-.alpha. -galactopyranoside or as it is sometimes referred to in the literature, 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose (hereinafter referred to as "sucralose") involves the substitution of chlorine atoms in the sucrose molecule in one of the five secondary hydroxyl positions and in two of the three primary hydroxyl positions. This particular selection of positions usually means that any synthetic route must involve the preparation of an intermediate sucrose derivative having the required positions available for chlorination while other positions are blocked. In particular, the reactive 6-position must not be chlorinated, while the 4-position must be rendered available for chlorination.
One route proposed in the literature (Fairclough et al, Carbohydrate Research 40 (1975) 285-298) involves the formation of the 6,1',6'-tritrityl derivative of sucrose, peracetylation of the molecule and then detritylation with migration of the 4-acetyl radical to the 6-position, to give 2,3,6,3',4'-penta-O-acetylsucrose which has the correct hydroxy groups unprotected. Subsequent reaction with an excess of sulfuryl chloride as the chlorinating agent provides the 4,1',6'-trichlorogalactosucrose penta-acetate which in turn yields sucralose on elimination of the acetyl groups. The chlorination proceeds with inversion of configuration at the 4-position. The 1' and 6'-positions freely rotate, but the 4-position cannot and the glucose ring is thus inverted at the 4-position yielding a galactose derivative so that the product is a galactosucrose. The reaction sequence involving the simultaneous detritylation and acetyl shift contains, in all, a relatively high number of stages, and the initial tritylation reaction is undesirable from an economic point of view.
Another route is set forth in U.S. Pat. No. 4,380,476 and comprises the steps of; (a) reacting sucrose with an acylating reagent under conditions to provide a mixture of acylated sucrose derivatives containing a major proportion of 6-monoacylated material: (b) optionally separating the 6-monoacylated sucrose derivative from other acylated derivatives before step (c); (c) reacting the monoacylated sucrose derivative with a Vilsmeier type chlorinating reagent capable of chlorinating at positions 1', 4 and 6' of a sucrose 6-acylate; and (d) deacylating and separating (in either order) the sucralose material formed.
A further process for preparing sucralose is set forth in U.S. Pat. No. 4,362,869. This process converts sucrose through a number of steps into sucralose. This process describes the sequential steps of (1) tritylation of sucrose to block the three primary alcohol groups; (2) acetylation of the five secondary alcohol groups as acetates; (3) detritylation of the three primary alcohol groups to deblock them; (4) acetyl migration from the 4-position to the 6-position; (5) chlorinating the desired alcohol groups at positions 4, 1', 6'; and (6) deblocking the remaining five alcohol groups by deacetylation thereby yielding sucralose.
A number of chlorinating agents are disclosed in U.S. Pat. No. 4,362,869 including a chlorinating reagent consisting of triarylphosphine/carbon tetrachloride, N,N-dialkyl (chloromethan-iminium) chlorides and dichlorophosphoranes as well as other prior art chlorinating reagents.
While generally satisfactory in some cases, the chlorinating reagents disclosed in the above processes do present some problems. In some cases, the yields may be erratic due to decomposition and charring of the resultant products may be observed. Some of the above reactions are not efficient yielding incompletely chlorinated materials and when pyridine is involved as a solvent, the reactions are expensive due to the cost of the pyridine, the difficulty in recovering same and chlorinated by-products are formed which reduce recovery efficiencies.
It is an object of the present invention to provide a process for the chlorination of carbohydrates and other alcohols.
It is a further object of the present invention to provide an improved process for the preparation of sucralose.
It is a still further object of the present invention to provide an improved process for the preparation of sucralose wherein the chlorinating agent is efficient and eliminates the use of pyridine as a solvent.
These and other objects of the present invention will become apparent to one skilled in the art from the detailed description given hereinafter.